Acquired Immune Deficiency Syndrome (AIDS) is one of the most feared diseases in the world today. Infection with the human immunodeficiency virus (HIV-1), believed to be the cause of AIDS is almost always fatal. Symptoms of the disease can take years to develop, thus facilitating the spread of this fatal disease by persons unknowingly harboring the virus. Treatments for AIDS are limited and have been unsuccessful in controlling the disease.
HIV-1 has been shown to preferentially infect cells expressing the CD4, a 55,000 dalton cell surface glycoprotein. This tropism is believed to result from interactions between the virus envelope gp120 and a high affinity binding site on the CD4 glycoprotein which permits viral adsorption- gp120 is part of the envelope glycoprotein gp160. This larger glycoprotein consists of two main glycoprotein portions - gp120 and gp41. gp120 is believed to be the outermost part of the complex made up of these two glycoproteins. gp41, the inner portion of the complex, is embedded in the viral membrane. Following the initial attachment of virus to the cell surface CD4 molecule, gp41 pierces the membranes of the target cell and initiates fusion. This interaction precedes viral entry, uncoating, and replication.
U.S. Pat. No. 4,520,113 issued May 28, 1985 to Gallo et al. discloses methods of detecting HTLV-III (now named HIV-1) in sera of AIDS and pre-AIDS patients. These methods detect the presence of antibodies in the patient's serum which bind to antigenic sites on HIV-1 or fractions of HIV-1, thus signalling the presence of the virus itself in the patient. A fraction known as gp41, a 41,000 dalton viral envelope protein was found to be particularly useful in the diagnostic methods of the invention because many persons having AIDS or pre-AIDS illnesses were found to have antibodies against this viral protein.
U.S. Pat. No. 4,725,669 issued Feb. 16, 1988 to Essex and Lee discloses novel polypeptides along with assays which use the polypeptides to detect infection of cells by human T-cell lymphotrophic virus-III (i.e. HIV-1). The polypeptides may be purified forms of glycoproteins found in the cell surface membrane of cells infected with human T-cell lymphotrophic virus-III. The polypeptides contain antigenic determinants immunologically cross-reactive with glycoproteins having a molecular weight of 120,000 daltons and 160,000 daltons which occur on the surface of cells infected with HTLV-III (HIV-1).
Treatment of individuals infected with HIV-1 has been complicated by the binding capacity of the virus to mammalian cells and the extreme toxicity of infection with the virus. The potential for inadvertently infecting healthy individuals with only partially inactivated whole HIV-1 or components of the virus as part of a vaccine is very high. One commercially available compound which is useful as an anti-infective agent is a form of CD4. The compound is believed to work because it binds the gp120 as tightly as the natural CD4. In this way, if given in high enough concentrations, the free (administered) CD4 will bind all of the viral gp120 and prevent its binding CD4 on host cells. Efforts to control the virus through drugs has not succeeded. Alternate means of treating individuals infected with HIV-1, as well as alternate means of preventing or inhibiting infection of cells with HIV-1 are needed which are not toxic to the individual infected with HIV-1 and are safe for individuals not infected with the virus.
A major problem with retroviral infections is the manner in which the retroviruses are able to subvert the host organism's immune response to the detriment of the host. This is illustrated most vividly by the effect of HIV infection on human helper T cells. HIV-1 infects cells by first binding to host cell CD4 molecules utilizing the vital envelope glycoprotein gp120, and subsequently fusing with the cell membrane. In an infected cell, gp120 is expressed on the surface of the cell, creating a potential target for cytolytic antibody responses. Superficially, an antibody response to gp120 would seem to be advantageous to the host. However, during HIV infection, large amounts of gp120 are also shed from infected cells, with subsequent binding to CD4 molecules on uninfected cells- These uninfected cells also become targets for cytolytic antibody binding and subsequent lysis. Among CD4 bearing cells in the host are helper T cells, the very cells necessary for the development of antibody responses. By shedding gp120 from infected cells, HIV is able to cripple an essential arm of the immune response that would lead to elimination of HIV.
Accordingly, it is an object of the invention to provide agents and methods to inhibit infection of cells by HIV-1. A further object is to provide polypeptides capable of effecting such inhibition. Another object is to interfere with the binding of HIV-1 to host cells. A further object is to provide methods for detecting the presence or HIV-1 In biological specimens or of detecting the presence of antibodies for HIV-1 in such specimens.
It would obviously be beneficial to the host develop antibody responses that are able to recognize and destroy infected cells, while leaving uninfected cells intact. Thus it is also an object of the invention to provide such antibodies. It is a further object of the invention to provide methods for the recognition of sites on retroviruses that are immunogenic and lead to the development of beneficial antibodies of this type. These and other objects will become apparent from a review of the instant specification.